Parkinson's disease is a prevalent neurodegenerative disorder characterized by tremors, rigidity, and bradykinesia. These symptoms arise from the degeneration of dopaminergic neurons in the substantia nigra. The cellular and molecular mechanisms responsible for neurodegeneration in Parkinson's disease remain poorly understood, although genetic and environmental factors both appear to play contributing roles. Recently, loss-of-function mutations in DJ-1, a gene of unknown function, were found to be responsible for an autosomal recessive form of Parkinson's disease. To explore the normal biological function of DJ-1, and the mechanism by which loss of DJ-1 function results in neurodegeneration, we propose to subject a pair of highly conserved Drosophila DJ-1 homologs (designated DJ-1a and DJ-1b) to mutational analysis. DJ-1a and DJ-1b function will be perturbed using P element mutagenesis, gene-targeting and double stranded RNA interference methods. The phenotypes resulting from perturbation of these genes will be fully characterized, including an analysis of dopaminergic neuron integrity. Additionally, we will characterize the global gene expression changes resulting from loss of DJ-1a and DJ-1b function and initiate screens for genetic modifiers of the DJ-1a and DJ-1b phenotypes to elucidate the biochemical pathways in which these genes function. This work should clarify the normal cellular role of DJ-1 and provide a foundation for further hypothesis-driven investigation of DJ-1 function.